Project Summary Despite advances in the treatment of acute myocardial infarction (MI), many patients still experience loss of cardiac muscle with subsequent adverse cardiac remodeling and heart failure. Stem cell therapy administered early after MI was designed to reduce heart failure by decreasing cell death and increasing the regeneration of new cardiac muscle and vascular cells. However, most trials achieved only modest clinical benefits. Growing evidence suggests that many of the beneficial effects of stem cells are due to exosomes and other paracrine factors (PFs) they secrete. These factors increase angiogenesis, decrease apoptosis, potentiate cell proliferation, promote cell migration, and as a result, turn on and turn up the body's intrinsic repair capac- ity. Delivery of these stem cell factors and their sustained presence at the injured site could limit damage, effect repair, and produce a significant and lasting clinical benefit. However, delivery vehicles that can sense the evolving needs of injured tissue and, in response, deliver the large and varying array of required factors have not been available. We created the Stem Cell Implantable Bioreactor (SCIB), a novel removable platform for in vivo production and delivery of stem cell PFs, to achieve this objective. The SCIB is placed in a central vein after reperfusion therapy for acute MI, and shelters stem cells within a protective semi-permeable pouch, shielding them from washout and immune attack, but allowing nutrients to enter and PFs to pass freely into the circulation and to the injured tissue. Stem cells in the SCIB act as factories that sense host signals and, in response, produce the entire library of potentially hundreds of PFs in the right sequence, concentration, combination, and duration required for healing. The first generation SCIB favorably reduced adverse cardiac remodeling after an anterior MI in pigs, but was impermeable to exosomes, had a limited stem cell capacity, and was not manufactured using clinical-grade materials. We formed Domicell LLC to develop a refined SCIB for human testing and commercialize the technology. In this SBIR Phase 1 application, we propose critical in vitro and in vivo studies that will support the development of a second generation SCIB using clinical-grade materials, with a higher stem cell capacity and permeability to all PFs including exosomes. At the conclusion of the proposed SBIR Phase 1 studies, Domicell LLC will have a clinical-grade SCIB product that will support a pivotal pre-clinical large animal study in SBIR Phase 2, the results of which will be used to apply to the FDA for first-in-man clinical trials. In the long term, Domicell LLC envisions that cell therapy based on implantable bioreactors will become a fundamentally new approach to deliver, on demand, cell-derived PFs for the treatment of both cardiac and non-cardiac diseases.